Significance We previously demonstrated that infant rhesus macaques infected with simian immunodeficiency virus (SIVmac) and receiving prolonged PMPA treatment develop viral mutants with 5-fold reduced susceptibility to PMPA. Surprisingly, animals stay healthy for a long period of time. This is in contrast to what we previously observed with AZT in this same animal model, where the clinical benefits of AZT therapy only lasted for as long as the virus remained AZT-sensitive. Objectives To determine the virulence and clinical implications of PMPA-resistant SIV in newborn macques. Results Two uncloned PMPA-resistant SIVmac isolates, SIVmac055 and SIVmac385 were each inoculated intravenously into a group of 6 newborn rhesus macaques; three weeks later, three animals of each group were started on prolonged PMPA treatment. All 6 untreated animals developed persistently high viremia and fatal immunodeficiency within 3 months. In contrast, the 6 PMPA-treated animals, despite having persistently high virus levels, survived significantly longer 5-9 months for the 3 SIVmac055-infected and _ 21 months for the 3 SIVmac385-infected infants. Thus, although PMPA-resistant SIV is fully virulent, PMPA treatment still offers strong therapeutic benefits for macaques infected with PMPA-resistant SIV. Our results suggest that the emergence of PMPA-resistant HIV mutants in human patients during prolonged PMPA therapy will not eliminate its therapeutic benefits. Future Directions Future studies will determine how PMPA keeps animals, which have high levels of PMPA-resistant virus alive for extended periods of time. Based on murine studies, we hypothesize that PMPA has, in addition to antiviral effects, also immunomodulatory effects through enhancement of natural killer cell activity. KEYWORDS PMPA, primate, pathogenesis, drug resistance, pediatrics